Substituted azetidinone compunds, processes for preparing the same, formulations and uses thereof

ABSTRACT

The present invention provides substituted azetidinone compounds, formulations and processes for preparing the same which can be useful for treating vascular conditions such as atherosclerosis or hypercholesterolemia, diabetes, obesity, stroke, demyelination and lowering plasma levels of sterols and/or stanols in a subject.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of priority from U.S. ProvisionalPatent Application Ser. No. 60/452,809, filed Mar. 7, 2003, incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to substituted azetidinone compoundsuseful for treating vascular and lipidemic conditions, and formulationsand processes related thereto.

Atherosclerotic coronary heart disease (CHD) represents the major causefor death and vascular morbidity in the western world. Risk factors foratherosclerotic coronary heart disease include hypertension, diabetesmellitus, family history, male gender, cigarette smoke and high serumcholesterol. A total cholesterol level in excess of 225-250 mg/dl isassociated with significant elevation of risk of CHD. The newly revisedNCEP ATP III low density lipoprotein (LDL-C) goal for patients with CHDor CHD risk equivalent is <100 mg/dL (2.59 mmol/L), for individuals withtwo or more risk factors is <130 mg/dL (3.37 mmol/L) and for individualswith fewer than two risk factors is <160 mg/dL (4.14 mmol/L).

The regulation of whole-body cholesterol homeostasis in mammals andanimals involves the regulation of dietary cholesterol and modulation ofcholesterol biosynthesis, bile acid biosynthesis and the catabolism ofthe cholesterol-containing plasma lipoproteins. The liver is the majororgan responsible for cholesterol biosynthesis and catabolism and, forthis reason, it is a prime determinant of plasma cholesterol levels. Theliver is the site of synthesis and secretion of very low densitylipoproteins (VLDL) which are subsequently metabolized to low densitylipoproteins (LDL) in the circulation. LDL are the predominantcholesterol-carrying lipoproteins in the plasma and an increase in theirconcentration is correlated with increased atherosclerosis. Whenintestinal cholesterol absorption is reduced, by whatever means, lesscholesterol is delivered to the liver. The consequence of this action isdecreased hepatic lipoprotein (VLDL) production and an increase in thehepatic clearance of plasma cholesterol, mostly as LDL. Thus, the neteffect of inhibiting intestinal cholesterol absorption is a decrease inplasma cholesterol levels and progression of atherosclerotic lesionformation.

U.S. Pat. Nos. 5,767,115, 5,624,920, 5,668,990, 5,656,624 and 5,688,787,respectively, disclose hydroxy-substituted azetidinone compounds andsubstituted β-lactam compounds useful for lowering cholesterol and/or ininhibiting the formation of cholesterol-containing lesions in mammalianarterial walls. U.S. Pat. No. 5,756,470, U.S. Patent Application No.2002/0137690, U.S. Patent Application No. 2002/0137689 and PCT PatentApplication No. WO 2002/066464 disclose sugar-substituted azetidinonesand amino acid substituted azetidinones useful for preventing ortreating atherosclerosis and reducing plasma cholesterol levels.

U.S. Pat. Nos. 5,846,966 and 5,661,145, respectively, disclosetreatments for inhibiting atherosclerosis and reducing plasmacholesterol levels using such hydroxy-substituted azetidinone compoundsor substituted 13-lactam compounds in combination with HMG CoA reductaseinhibitor compounds, which act by blocking hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase (the rate-limiting enzyme in hepaticcholesterol synthesis).

Despite recent improvements in the treatment of vascular disease, thereremains a need for improved compounds, compositions and treatments forhyperlipidaemia, atherosclerosis and other vascular conditions thatprovide more efficient delivery of treatment.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a compound representedby the structural formula (I):

or pharmaceutically acceptable isomers, salts, solvates or esters of thecompound of Formula (I),wherein in Formula (I) above:

X, Y and Z can be the same or different and each is independentlyselected from the group consisting of —CH₂—, —CH(alkyl)- and—C(alkyl)₂-;

Q¹ and Q² can be the same or different and each is independentlyselected from the group consisting of H, —(C₀-C₃₀ alkylene)-G, —OR⁶,—OC(O)R⁶, —OC(O)OR⁹, —OC(O)NR⁶R⁷, and -L-M;

Q³ is 1 to 5 substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, —(C₀-C₃₀ alkylene)-G, —(C₀-C₁₀alkylene)-OR⁶, —(C₀-C₁₀ alkylene)-C(O)R⁶, —(C₀-C₁₀ alkylene)-C(O)OR⁶,—(C₀-C₁₀ alkylene)-OC(O)R⁶, —(C₀-C₁₀ alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶,—CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —O—(C₀-C₁₀alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)(aryl)-N—N═N⁻,—OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —(C₀-C₁₀ alkylene)-C(O)NR⁶R⁷, —(C₀-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl, 25benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M;

Q⁴ is 1 to 5 substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, —(C₀-C₃₀ alkylene)-G, —(C_(o)-C₁₀alkylene)-OR⁶, —(C₀-C₁₀ alkylene)-C(O)R⁶, —(C₀-C₁₀ alkylene)-C(O)OR⁶,—(C₀-C₁₀ alkylene)-OC(O)R⁶, —(C₀-C₁₀ alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶,—CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —O—(C₀-C₁₀alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)(aryl)-N—N═N—,—OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —(C₀-C₁₀ alkylene)-C(O)NR⁶R⁷, —(C₀-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyidioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M;

Q⁵ is 1 to 5 substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, —(C₀-C₃₀ alkylene)-G, —(C₀-C₁₀alkylene)-OR⁶, —(C₀-C₁₀ alkylene)-C(O)R⁶, —(C₀-C₁₀ alkylene)-C(O)OR⁶,—(C₀-C₁₀ alkylene)-OC(O)R⁶, —(C₀-C₁₀ alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶,—CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —O—(C₀-C₁₀alkylene)-C(O)NR⁶NR⁷C(O)OR⁶. —O—(C₁-C₁₀ alkylene)-C(O)(aryl)-N—N═N⁻,—OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —(C₀-C₁₀ alkylene)-C(O)NR⁶R⁷, —(C₀-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₀-C₁₀alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶, —CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —O—(C₀-C₁₀alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)(aryl)-N—N═N⁻,—OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —(C₀-C₁₀ alkylene)-C(O)NR⁶R⁷, —(C₀-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R , —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M;

Q⁵ is 1 to 5 substituents independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, —(C₀-C₃₀ alkylene)-G, —(C₀-C₁₀alkylene)-OR⁶, —(C₀-C₁₀ alkylene)-C(O)R⁶, —(C₀-C₁₀ alkylene)-C(O)OR⁶,—(C₀-C₁₀ alkylene)-OC(O)R⁶, —(C₀-C₁₀ alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶,—CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —O—(C₀-C₁₀alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)(aryl)-N—N═N⁻,—OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —(C₀-C₁₀ alkylene)-C(O)NR⁶R⁷, —(C₀-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R ⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyidioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M;

wherein optionally one or more carbon atoms of the —(C₀-C₃₀ alkylene)-radical of Q¹, Q², Q³, Q⁴ and Q⁵ is independently replaced by —O—,—C(O)—, —CH═CH—,

—N(alkyl)-, —N(alkylaryl)- or —NH—;

G is selected from the group consisting of a sugar residue, disugarresidue, trisugar residue, tetrasugar residue, sugar acid, amino sugar,amino acid residue, oligopeptide residue comprising 2 to 9 amino acids,trialkylammoniumalkyl radical and —S(O)₂—OH, wherein optionally thesugar residue, disugar residue, trisugar residue, tetrasugar residue,sugar acid, amino sugar, amino acid residue or oligopeptide residue of Gis substituted with -L-M;

L is selected from the group consisting of

wherein Me is methyl;

M is selected from the group consisting of

R² and R³ can be the same or different and each is independentlyselected from the group consisting of hydrogen, alkyl and aryl;

R⁶, R⁷ and R⁸ can be the same or different and each is independentlyselected from the group consisting of hydrogen, alkyl, aryl andarylalkyl; and

each R⁹ is independently alkyl, aryl or arylalkyl.

each R¹⁰ is independently H or alkyl;

q is 0 or 1;

r is 0 or 1;

m, n and p are independently selected from 0, 1, 2, 3 or 4; providedthat at least one of q and r is 1, and the sum of m, n, p, q and r is 1,2, 3, 4, 5 or 6; and provided that when p is 0 and r is 1, the sum of m,q and n is 1, 2, 3, 4 or 5;

x1 is 1 to 10;

x2 is 1 to 10;

x3 is 1 to 10;

x4 is 1 to 10;

x5 is 1 to 10;

x6 is 1 to 10; and

x7 is 1 to 10;

with the proviso that at least one of Q¹, Q², Q³, Q⁴ and Q⁵ is -L-M orthe sugar residue, disugar residue, trisugar residue, tetrasugarresidue, sugar acid, amino sugar, amino acid residue or oligopeptideresidue of G is substituted with -L-M.

Pharmaceutical formulations or compositions for the treatment orprevention of a vascular condition, diabetes, obesity, stroke, loweringa concentration of a sterol or stanol in plasma of a mammal, preventingdemyelination or treating Alzheimer's disease and/or regulating levelsof amyloid β peptides in a subject comprising a therapeuticallyeffective amount of the above compounds and a pharmaceuticallyacceptable carrier also are provided.

Methods of treating or preventing a vascular condition, diabetes,obesity, stroke, lowering a concentration of a sterol or stanol inplasma of a mammal, preventing demyelination or treating Alzheimer'sdisease and/or regulating levels of amyloid β peptides in a subjectcomprising the step of administering to a subject in need of suchtreatment an effective amount of the above compounds of Formula (I) alsoare provided.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.”

DETAILED DESCRIPTION

In its many embodiments, the present invention provides a novel class ofcompounds of Formula (I) above, processes for producing such compounds,pharmaceutical formulations or compositions comprising one or more ofsuch compounds, methods of preparing the same, and methods of treatment,prevention, inhibition or amelioration of one or more conditions ordiseases associated with vascular conditions or other conditions such asare discussed in detail below.

The compounds of Formula (I) are capable of being metabolized in vivo toform a sterol and/or stanol absorption inhibitor compound and a sterolbiosynthesis inhibitor compound. As used herein, “sterol absorptioninhibitor” means a compound capable of inhibiting the absorption of oneor more sterols, including but not limited to cholesterol andphytosterols (such as sitosterol, campesterol, stigmasterol andavenosterol) when administered in a therapeutically effective (sterolabsorption inhibiting) amount to a subject or human. “Stanol absorptioninhibitor” means a compound capable of inhibiting the absorption of oneor more 5α-stanols (such as cholestanol, 5α-campestanol, 5α-sitostanol)when administered in a therapeutically effective (stanol absorptioninhibiting) amount to a subject or human. The sterol or stanolabsorption inhibitor can inhibit the absorption of cholesterol from theintestinal lumen into enterocytes, leading to a decrease in the deliveryof intestinal sterol or stanol, respectively, to the liver. “Sterolbiosynthesis inhibitor” means a compound, such as a3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor,that blocks hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, whichis the rate-limiting enzyme in hepatic cholesterol synthesis.

In an alternative embodiment, compounds of Formula (I) can have dualfunctionality, i.e., can exhibit sterol and/or stanol absorptioninhibiting properties and also block hydroxymethylglutaryl coenzyme A(HMG-CoA) reductase.

Referring now to Formula (I), in one embodiment of the presentinvention, X, Y and Z are each —CH₂—.

The sum of m, n, p, q and r is preferably 2, 3 or 4, more preferably 3.Also preferred are compounds of Formula (I) in which p, q and n are eachzero, r is 1 and m is 2 or 3.

In one embodiment, m, n and r are each zero, q is 1, p is 2, and Z is—CH₂—. Also preferred are compounds wherein m, n and r are each zero, qis 1, p is 2, and Z is —CH₂—, Q¹ is —OR⁶, wherein R⁶ is hydrogen and Q⁵is fluorine.

R² and R³ are each preferably hydrogen.

In one embodiment, Q¹ and Q² can be —OR⁶ wherein R⁶ is hydrogen, or agroup readily metabolizable to a hydroxyl (such as —O(CO)R⁶, —O(CO)OR⁹and —O(CO)NR⁶R⁷, defined above).

In another embodiment Q⁴ is halo or —OR⁶.

In another embodiment, Q¹ is —OR⁶ wherein R⁶ is H.

In yet another embodiment, Q¹ is -L-M.

In another embodiment, Q² is -L-M.

In another embodiment, Q³ is -L-M.

In another embodiment, Q⁴ is -L-M.

In another embodiment, Q⁵ is -L-M.

In another embodiment, Q⁵ is halo.

In another embodiment, Q¹, Q², Q³, Q⁴ or Q⁵ is independently —(C₀-C₃₀alkylene)-G. In another embodiment, Q¹, Q² or Q³ is independently—(C₀-C₃₀ alkylene)-G. In another embodiment, Q¹ or Q³ is independently—(C₀-C₃₀ alkylene)-G.

In one embodiment, G is selected from the group consisting of:

(sugar residues)

wherein R, R^(a) and R^(b) can be the same or different and each isindependently selected from the group consisting of H, —OH, halo, —NH₂,azido, alkoxyalkoxy or —W—R³⁰;

W is independently selected from the group consisting of —NH—C(O)—,—O—C(O)—, —O—C(O)—N(R³¹)—, —NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—;

R²¹ and R^(6a) can be the same or different and each is independentlyselected from the group consisting of H, alkyl, acetyl, aryl andarylalkyl;

R^(3a), R^(4a), R^(5a), R^(7a), R^(3b) and R^(4b) can be the same ordifferent and each is independently selected from the group consistingof H, alkyl, acetyl, arylalkyl, —C(O)alkyl and —C(O)aryl;

R³⁰ is independently selected from the group consisting ofR³²-substituted T, R³²-substituted-T-alkyl, R³²-substituted-alkenyl,R³²-substituted-alkyl, R³²-substituted-cycloalkyl andR³²-substituted-cycloalkylalkyl;

R³¹ is independently selected from the group consisting of H and alkyl;

T is independently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl;

R³² is 1 to 3 substituents which are each independently selected fromthe group consisting of H, halo, alkyl, —OH, phenoxy, —CF₃, —NO₂,alkoxy, methylenedioxy, oxo, alkylsulfanyl, alkylsulfinyl,alkylsulfonyl, —N(CH₃)₂, —C(O)-NHalkyl, —C(O)-N(alkyl)₂, —C(O)-alkyl,—C(O)-alkoxy and pyrrolidinylcarbonyl; or R³² is a covalent bond andR³¹, the nitrogen to which it is attached and R³² form a pyrrolidinyl,piperidinyl, N-methyl-piperazinyl, indolinyl or morpholinyl group, or aalkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group.

In another embodiment, G is selected from:

wherein Ac is acetyl and Ph is phenyl.

In another embodiment, optionally one or more carbon atoms of the—(C₀-C₃₀ alkylene)- radical of Q¹, Q², Q³, Q⁴ and Q⁵ is independentlyreplaced by —O—, —C(O)—, —CH═CH—,

—N(alkyl)-, —N(alkylaryl)- or —NH—, preferably —O—.

The —(C₀-C₃₀ alkylene)-G substituent is preferably in the 4-position ofthe phenyl ring to which it is attached.

In one embodiment, L is

Preferably, x1 is 1 to 3 and more preferably x1 is 3.

In another embodiment, L is

Preferably, x5 is 1 to 3 and more preferably x5 is 3.In one embodiment, M is

In another embodiment, M is

In another embodiment, M is

In another embodiment, M is

In another embodiment, M is

One embodiment of the present invention is a compound of Formula (II)

Another embodiment of the present invention is a compound of Formula(III)

Another embodiment of the present invention is a compound of Formula(IV)

Another embodiment of the present invention is a compound of Formula (V)

Another embodiment of the present invention is a compound of Formula(VI)

Another embodiment of the present invention is a compound of Formula(VII)

Another embodiment of the present invention is a compound of Formula(VIII)

Another embodiment of the present invention is a compound of Formula(XI)

Another embodiment of the present invention is a compound of Formula (X)

Another embodiment of the present invention is a compound of Formula(XI)

Another embodiment of the present invention is a compound of Formula(XII)

Another embodiment of the present invention is a compound of Formula(XIII)

Another embodiment of the present invention is a compound of Formula(XIV)

When any of the compounds of Formulae(II-XIV) is metabolized, one of thecompounds (sterol and/or stanol absorption inhibitor) which can beformed is represented by Formula (XV) (ezetimibe) below:

or pharmaceutically acceptable salts, esters or solvates of the compoundof Formula (XV).

Alternatively or additionally, when any of the compounds of Formulae(II), (VII) or (IX-XIII) is metabolized, compounds (sterol biosynthesisinhibitors) which can be formed are represented by Formulae (XVI) (openacid form of simvastatin) and (XVII) (simvastatin) below:

Alternatively or additionally, when any of the compounds of Formulae(III) or (VIII) is metabolized, compounds (sterol biosynthesisinhibitors) which can be formed are represented by Formulae (XVIII)(openacid lovastatin) and (IX)(lovastatin) below:

Similarly, when the compound of Formula (IV) is metabolized, compounds(sterol biosynthesis inhibitors) which can be formed includeatorvastatin and the open acid form of atorvastatin. Likewise, when thecompound of Formula (V) is metabolized, compounds (sterol biosynthesisinhibitors) which can be formed include rosuvastatin and the open acidform of rosuvastatin. Similarly, when the compound of Formula (VI) ismetabolized, compounds (sterol biosynthesis inhibitors) which can beformed include pravastatin and the open acid form of pravastatin.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Subject” includes both mammals and non-mammalian animals.

“Mammal” includes humans and other mammalian animals.

The above statements, wherein, for example, Q¹ and Q² are said to beindependently selected from a group of substituents, means that Q¹ andQ² are independently selected, but also that where an Q¹ or Q² variableoccurs more than once in a molecule, those occurrences are independentlyselected (e.g., if Q¹ is —OR⁶ wherein R⁶ is hydrogen, Q² can be —OR⁶wherein R⁶ is alkyl). Those skilled in the art will recognize that thesize and nature of the substituent(s) will affect the number ofsubstituents that can be present.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties. It should be noted that any atomwith unsatisfied valences in the text, schemes, examples and tablesherein is assumed to have the hydrogen atom(s) to satisfy the valences.

The following definitions apply regardless of whether a term is used byitself or in combination with other terms, unless otherwise indicated.Therefore, the definition of “alkyl” applies to “alkyl as well as the“alkyl” portions of “hydroxyalkyl”, “haloalkyl”, “alkoxy”, etc.

As used herein, the term “alkyl” means an aliphatic hydrocarbon groupthat can be straight or branched and comprises 1 to about 20 carbonatoms in the chain. Preferred alkyl groups comprise 1 to about 12 carbonatoms in the chain. More preferred alkyl groups comprise 1 to about 6carbon atoms in the chain. “Branched” means that one or more lower alkylgroups such as methyl, ethyl or propyl, are attached to a linear alkylchain. “Lower alkyl” means a group having about 1 to about 6 carbonatoms in a chain that may be straight or branched. The alkyl can besubstituted by one or more substituents independently selected from thegroup consisting of halo, aryl, cycloalkyl, cyano, hydroxy, alkoxy,alkylthio, amino, —NH(alkyl), —NH(cycloalkyl), —N(alkyl)₂ (which alkylscan be the same or different), carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl,fluoromethyl, trifluoromethyl and cyclopropylmethyl.

“Alkenyl” means an aliphatic hydrocarbon group (straight or branchedcarbon chain) comprising one or more double bonds in the chain and whichcan be conjugated or unconjugated. Useful alkenyl groups can comprise 2to about 15 carbon atoms in the chain, preferably 2 to about 12 carbonatoms in the chain, and more preferably 2 to about 6 carbon atoms in thechain. “Lower alkenyl” means 2 to about 6 carbon atoms in the chain thatcan be straight or branched. The alkenyl group can be substituted by oneor more substituents independently selected from the group consisting ofhalo, alkyl, aryl, cycloalkyl, cyano and alkoxy. Non-limiting examplesof suitable alkenyl groups include ethenyl, propenyl, n-butenyl,3-methylbut-enyl and n-pentenyl.

Where an alkyl or alkenyl chain joins two other variables and istherefore bivalent, the terms alkylene and alkenylene, respectively, areused.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Useful alkoxy groups can comprise 1 to about 12carbon atoms, preferably 1 to about 6 carbon atoms. Non-limitingexamples of suitable alkoxy groups include methoxy, ethoxy andisopropoxy. The alkyl group of the alkoxy is linked to an adjacentmoiety through the ether oxygen.

“Alkoxyarylalkoxy” means an alkyl-O-aryl-alkylene-O— group in which thealkyl, alkylene and aryl groups are as previously described. Usefulalkoxyarylalkoxy groups can comprise 7 to about 26 carbon atoms,preferably 7 to about 12 carbon atoms. A non-limiting example of asuitable alkoxyarylalkoxy group is methoxybenzyloxy. Thealkoxyarylalkoxy is linked to an adjacent moiety through the etheroxygen.

“Alkoxycarbonylalkoxy” means an alkyl-O—C(O)-alkylene-O— group in whichthe alkyl and alkylene groups are as previously described. Usefulalkoxycarbonylalkoxy groups can comprise 3 to about 12 carbon atoms,preferably 3 to about 8 carbon atoms. A non-limiting example of asuitable alkoxycarbonylalkoxy group is CH₃CH₂—O—C(O)—CH₂—O—. Thealkoxycarbonylalkoxy is linked to an adjacent moiety through the etheroxygen.

“Alkoxyiminoalkyl” means an alkyl-O—N═CH-alkylene-group in which thealkyl IS and alkylene groups are as previously described. Usefulalkoxyiminoalkyl groups can comprise 2 to about 12 carbon atoms,preferably 2 to about 8 carbon atoms. The alkoxyiminoalkyl is linked toan adjacent moiety through the alkylene group.

“Alkyldioyl” means an ROC(O)-alkylene-C(O)—O— group in which R is alkylor H and the alkylene group is as previously described. Usefulalkyldioyl groups can comprise 2 to about 12 carbon atoms, preferably 2to about 8 carbon atoms. Non-limiting examples of suitable alkyldioylgroups include 1,3-propanediol. The alkyldioyl is linked to an adjacentmoiety through the ester oxygen.

“Alkynyl” means an aliphatic hydrocarbon group comprising at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.The alkynyl group may be substituted by one or more substituents whichmay be the same or different, each substituent being independentlyselected from the group consisting of alkyl, aryl and cycloalkyl.

“Allyloxy” means H₂C═CH—O—. The allyloxy is linked to an adjacent moietythrough the ether oxygen.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be substituted with one or more“ring system substituents” which may be the same or different, and areas defined herein. Non-limiting examples of suitable aryl groups includephenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. “Arylene”means a bivalent phenyl group, including ortho, meta andpara-substitution.

“Aralkyl” or “arylalkyl” means an aryl-alkylene-group in which the aryland alkylene are as previously described. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, phenethyl and naphthlenylmethyl. The aralkyl is linkedto an adjacent moiety through the alkylene group.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen. “Aralkoxy” or “arylalkyloxy” means an aralkyl-O— groupin which the aralkyl group is as previously described. Non-limitingexamples of suitable aralkoxy groups include benzyloxy and 1- or2-naphthalenemethoxy. The bond to the parent moiety is through the etheroxygen. “Aralkoxycarbonyl” means an aralkoxy-C(O)— group in which thearalkoxy group is as previously described.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1- and 2-naphthoyl.

“Aroyloxy” means an aroyl-O— group in which the aroyl group is aspreviously described. The bond to the parent moiety is through the etheroxygen. Non-limiting examples of suitable groups include benzoyloxy and1- and 2-naphthoyloxy.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined below. Non-limiting examples of suitable monocyclic cycloalkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalinyl, norbornyl, adamantyl and the like. “Cycloalkylene” refersto a corresponding bivalent ring, wherein the points of attachment toother groups include all positional isomers.

“Dioxolanyl” means

“Halo” refers to fluorine, chlorine, bromine or iodine radicals.Preferred are fluoro, chloro or bromo, and more preferred are fluoro andchloro.

“Heteroaryl” means a monocyclic or multicyclic aromatic ring system ofabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the atoms in the ring system is/are atomsother than carbon, for example nitrogen, oxygen or sulfur. Theheteroatom(s) interrupt a carbocyclic ring structure and have asufficient number of delocalized pi electrons to provide aromaticcharacter, provided that the rings do not contain adjacent oxygen and/orsulfur atoms. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein. The prefix aza, oxa or thia before the heteroarylroot name means that at least a nitrogen, oxygen or sulfur atomrespectively, is present as a ring atom. A nitrogen atom of a heteroarylcan be oxidized to form the corresponding N-oxide. All regioisomers arecontemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl. Examples ofuseful 6-membered heteroaryl groups include pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl and the like and the N-oxides thereof. Examplesof useful 5-membered heteroaryl rings include furyl, thienyl, pyrrolyl,thiazolyl, isothiazolyl, imidazolyl, pyrazolyl and isoxazolyl. Usefulbicyclic groups are benzo-fused ring systems derived from the heteroarylgroups named above, e.g., quinolyl, phthalazinyl, quinazolinyl,benzofuranyl, benzothienyl and indolyl.

“Heteroarylalkyl” or “heteroaralkyl” means a heteroaryl-alkylene-groupin which the heteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl group. Non-limiting examples ofsuitable heteroaralkyl groups include pyridylmethyl, 2-(furan-3-yl)ethyland quinolin-3-ylmethyl. The bond to the parent moiety is through thealkylene. “Heteroarylalkoxy” means a heteroaryl-alkylene-O— group inwhich the heteroaryl and alkylene are as previously described.

“Heterocyclyl” means a non-aromatic saturated monocyclic or multicyclicring system comprising about 3 to about 10 ring atoms, preferably about5 to about 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur, alone or in combination. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Preferred heterocyclyls containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom respectively is present as a ring atom. The heterocyclyl can beoptionally substituted by one or more “ring system substituents” whichmay be the same or different, and are as defined herein. The nitrogen orsulfur atom of the heterocyclyl can be optionally oxidized to thecorresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples ofsuitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, and the like.

“Heterocyclylalkyl” means a heterocyclyl-alkylene-group in which theheterocyclyl and alkylene groups are as previously described. Preferredheterocyclylalkyls contain a lower alkylene group. The bond to theparent moiety is through the alkylene. “Heterocyclylcarbonyl” means aheterocyclyl-C(O)— group in which the heterocyclyl is as previouslydescribed. Preferred heterocyclylcarbonyls contain a lower alkyl group.The bond to the parent moiety is through the carbonyl.“Heterocyclylcarbonylalkoxy” means a heterocyclyl-C(O)-alkoxy-group inwhich the heterocyclyl and alkoxy are as previously described.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system that, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl,alkylheteroaryl, heteroaralkenyl, hydroxy, hydroxyalkyl, alkoxy,aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl,arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,heteroarylsulfinyl, alkylthio, arylthio, heteroarylthio, aralkylthio,heteroaralkylthio, cycloalkyl, cycloalkenyl, heterocyclyl,heterocyclenyl, Y₁Y₂N—, Y₁Y₂N-alkyl-, Y₁Y₂NC(O)— and Y₁Y₂NSO₂—, whereinY₁ and Y₂ may be the same or different and are independently selectedfrom the group consisting of hydrogen, alkyl, aryl, and aralkyl.

“Sugar residue” means a moiety derived from an aldose or ketose that has3 to 7 carbon atoms and may belong to the D or L series. Non-limitingexamples of suitable aldoses from which the sugar residue can be formedinclude glucose, mannose, galactose, ribose, erythrose andglyceraldehydes. A non-limiting example of a suitable ketose from whichthe sugar residue can be formed is fructose.

“Disugar residue” means a moiety derived from a sugar that can behydrolyzed to two monosaccharide molecules. Non-limiting examples ofsuitable compounds from which the disugar residue can be formed includemaltose, lactose, cellobiose and sucrose.

Examples of sugar residues and disugar residues include those moieties Glisted in detail above.

Di-, tri- or tetrasaccharides are formed by acetal-like binding of twoor more sugars. The bonds may be in α or β form. “Trisugar residue”means a moiety derived from a sugar that can be hydrolyzed to threemonosaccharide molecules. “Tetrasugar residue” means a moiety derivedfrom a sugar that can be hydrolyzed to four monosaccharide molecules.

If the sugar is substituted, the substitution is preferably at thehydrogen atom of an OH group of the sugar.

“Sugar acid” means an sugar residue, such as can be formed fromglucuronic acid, galacturonic acid, gluconic acid, galactonic acid,mannonic acid, glucaric acid and galactaric acid.

“Amino sugar” means an amino-substituted sugar residue such as can beformed from glucosamine, galactosamine, glucamine or3-amino-1,2-propanediol.

Suitable protective groups for the hydroxyl groups of the sugars includebenzyl, acetyl, benzoyl, pivaloyl, trityl, tert-butyldimethylsilyl,benzilidene, cyclohexidene or isopropylidene protective groups.

“Amino acid residue” means a moiety derived from an amino acid. Theamino acid moiety can be prepared from the D or L forms of the aminoacid. Non-limiting examples of suitable amino acids from which the aminoacid residue can be prepared include alanine, arginine, asparagine,aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine,histidine, hydroxylysine, hydroxyproline, isoleucine, leucine, lysine,methionine, phenylanine, proline, serine, threonine, tryptophane,tyrosine, valine, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine,2-aminobutyric acid, 4-aminobutyric acid, piperidino carboxylic acid,6-aminocaproic acid, 2-aminoheptanoic acid, 2-(2-thienyl)glycine,penicillamine, N-ethylasparagine, 2-aminoisobutyric acid,2-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid,desmosine, 2,2-diaminopimelic acid, 2,3-diaminopropioninc acid,N-ethylglycine, 3-(2-thienyl)alanine, sarcosine, N-methylisoleucine,6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine andN-methylglycine.

“Oligopeptide residue” means the residue of a peptide constructed of 2to 9 of the amino acids mentioned above.

“Trialkylammonium alkyl radical” means the group

wherein n1 is 0 to 10 and Alk₁, Alk₂ and Alk₃can be the same ordifferent and each is a straight or branched alkyl radical having 1 to20 carbon atoms.

Compounds of the invention have at least one asymmetrical carbon atomand therefore all isomers, including enantiomers, stereoisomers,rotamers, tautomers and racemates of the compounds of Formula (I) (wherethey exist) are contemplated as being part of this invention. Theinvention includes d and I isomers in both pure form and in admixture,including racemic mixtures. Isomers can be prepared using conventionaltechniques, either by reacting optically pure or optically enrichedstarting materials or by separating isomers of a compound of the FormulaI. Isomers may also include geometric isomers, e.g., when a double bondis present. Polymorphous forms of the compounds of Formula (I), whethercrystalline or amorphous, also are contemplated as being part of thisinvention.

Those skilled in the art will appreciate that for some of the compoundsof the Formula I, one isomer will show greater pharmacological activitythan other isomers.

Compounds of the invention with an amino group can form pharmaceuticallyacceptable salts with organic and inorganic acids. Examples of suitableacids for salt formation are hydrochloric, sulfuric, phosphoric, acetic,citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic,maleic, methanesulfonic and other mineral and carboxylic acids wellknown to those in the art. The salt is prepared by contacting the freebase form with a sufficient amount of the desired acid to produce asalt. The free base form may be regenerated by treating the salt with asuitable dilute aqueous base solution such as dilute aqueous sodiumbicarbonate. The free base form differs from its respective salt formsomewhat in certain physical properties, such as solubility in polarsolvents, but the salt is otherwise equivalent to its respective freebase forms for purposes of the invention.

Certain compounds of the invention are acidic (e.g., those compoundswhich possess a carboxyl group). These compounds form pharmaceuticallyacceptable salts with inorganic and organic bases. Examples of suchsalts are the sodium, potassium, calcium, aluminum, gold and silversalts. Also included are salts formed with pharmaceutically acceptableamines such as ammonia, alkyl amines, hydroxyalkylamines,N-methylglucamine and the like.

Compounds of the invention with a carboxylic acid group can formpharmaceutically acceptable esters with an alcohol. Examples of suitablealcohols include methanol and ethanol.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof (e.g., a prodrug on being brought to the physiological pH orthrough enzyme action is converted to the desired drug form). Adiscussion of prodrugs is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S.Symposium Series, and in Bioreversible Carriers in Drug Design, (1987)Edward B. Roche, ed., American Pharmaceutical Association and PergamonPress, both of which are incorporated herein by reference thereto.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

Generally, the azetidinone portion of the compounds of Formula (I) canbe prepared by a variety of methods well known to those skilled in theart, for example such as are disclosed in U.S. Pat. Nos. 5,631,365,5,767,115, 5,846,966, 6,207,822, PCT Patent Application No. 02/079174and PCT Patent Application WO 93/02048, each of which is incorporatedherein by reference, and in the Example below. Preferably theazetidinone is prepared from ezetimibe, such as can be prepared byroutine separation methods from ZETIA® ezetimibe formulation that iscommercially available from Schering-Plough Corporation.

The statin compound for preparing the -M portion of the molecule can beprepared by a variety of methods, for example the statin compound forpreparing M1 can be prepared by methods such as are disclosed in PCT WO98/12188, U.S. Pat. Nos. 5,763,653, 5,763,646, 4,444,784, 4,582,915,4,820,850, or by routine separation methods from ZOCOR® simvastatinformulation which is commercially available from Merck & Co. Inc. Thecompound for preparing M2 can be prepared by methods such as aredisclosed in U.S. Pat. Nos. 4,231,938, 4,294,926, U.S. Pat. Nos.5,763,653, 4,323,648, 4,916,239, 5,763,646 or by routine separationmethods from MEVACOR® lovastatin formulation which is commerciallyavailable from Merck & Co. Inc. The compound for preparing M3 can beprepared by methods such as are disclosed in U.S. Pat. Nos. 5,273,995,4,681,893, 5,969,156 or by routine separation methods from LIPITOR®atorvastatin formulation which is commercially available from Pfizer.The compound for preparing M4 can be prepared by methods such as aredisclosed in U.S. Pat. No. 5,260,440 or by routine separation methodsfrom CRESTOR® rosuvastatin formulation that is commercially availablefrom AstraZeneca. The compound for preparing M5 can be prepared bymethods such as are disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080.The compound for preparing M6 can be prepared by methods such as aredisclosed in U.S. Pat. Nos. 5,872,130, 5,856,336, 5,011,930 and5,854,259. The compound for preparing M7 can be prepared by methods suchas are disclosed in U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629 or byroutine separation methods from PRAVACHOL® pravastatin formulation whichis commercially available from Bristol-Myers Squibb. The compound forpreparing M8 can be prepared by methods such as are disclosed in U.S.Pat. Nos. 5,354,772 and 4,739,073 or by routine separation methods fromLESCOL® fluvastatin formulation that is commercially available fromNovartis.

The azetidinone portion of the molecule and -M portion of the moleculecan be linked by linker -L- as shown for example in Schemes 2-6 below. Anon-limiting example of a suitable compound for preparing linker

is from N-Boc-propargylamine as shown below:

wherein Tf is trifluoromethanesulfonate.A non-limiting example of a suitable compound for preparing linker

is from 3-bromopropylamine as shown below:

A non-limiting example of a suitable compound for preparing linker

is from 3-bromopropan-1-ol trimethylsilylether as shown below:

Non-limiting examples of suitable compounds for preparing linker

are from chloroacetylchloride or 6-chlorohexanoyl chloride,respectively, as shown below:

Non-limiting examples of suitable compounds for preparing linker

are from N-Boc-β-alanine, N-Boc glycine andN-Boc-6-aminocaproic acid,respectively, in a manner as shown below:

Non-limiting examples of suitable compounds for preparing linker

are from acetoxyethyidimethylchlorosilane and1-chloro-(allyl)dimethylsilane, respectively, as shown below:

A non-limiting example of a suitable compound for preparing linker

is from acetoxyethyldimethylchlorosilane as shown above and with furthertreatment of the corresponding free alcohol withmethanesulfonylchloride, displacement of the resulting mesyl group withsodium azide, and reduction of the azide to give the amine as shownbelow:

In general, the compounds of Formula (I) can be prepared through thegeneral routes described below in Schemes 2-5.

Generally, in Scheme 2, treatment of the starting azetidinone (forexample ezetimibe 6) with an amino acid in which the amine functionalitycan be blocked with a suitable protective group such as a butoxycarbonyl(Boc) and an amide coupling reagent such as1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide gives rise to theprotected amino ester which upon treatment with mild acid such astrifluoroacetic acid gives the desired amine-substituted azetidinone 7.Selection of solvents and additives for the amide coupling reaction mayvary and would be obvious to one skilled in the art. Amine-substitutedazetidinone 7 is reacted with statin 8 (for example simvastatin) andpyridine to form compound 9 of the present invention.

Generally, in Scheme 3, treatment of amine-substituted azetidinone 7with the carboxylate salt of a statin such as rosuvastatin 10 in thepresence of an amide coupling reagent such as1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide forms compound 11 of thepresent invention.

Generally, in Scheme 4, treatment of amine-substituted azetidinone 7with the carboxylate salt of a statin such as pravastatin 12 in thepresence of an amide coupling reagent such as1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide forms compound 13 of thepresent invention.

Generally, in Scheme 5, treatment of amine-substituted azetidinone 7with the free carboxylic acid of a statin such as atorvastatin 14 in thepresence of an amide coupling reagent such as1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide forms compound 15 of thepresent invention.

The daily dose of the compound of Formula (I) can range from about 0.1to about 1000 mg per day, preferably about 0.25 to about 100 mg/day, andmore preferably about 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 mgper day, given in a single dose or 2-4 divided doses. The exact dose,however, is determined by the attending clinician and is dependent onthe potency of the compound administered, the age, weight, condition andresponse of the patient. The phrases “effective amount” and“therapeutically effective amount” mean that amount of a compound ofFormula I, and other pharmacological or therapeutic agents describedbelow, that will elicit a biological or medical response of a tissue,system, animal or mammal that is being sought by the administrator (suchas a researcher, doctor or veterinarian) which includes alleviation ofthe symptoms of the condition or disease being treated and theprevention, slowing or halting of progression of one or more conditions,for example vascular conditions, such as hyperlipidaemia (for exampleatherosclerosis, hypercholesterolemia or sitosterolemia), vascularinflammation, stroke, diabetes, obesity and/or to reduce the level ofsterol(s) (such as cholesterol) or stanol(s) in the plasma of a subject.As used herein, “vascular” comprises cardiovascular, cerebrovascular,peripheral vascular and combinations thereof. The formulations orcompositions, combinations and treatments of the present invention canbe administered by any suitable means which produce contact of thesecompounds with the site of action in the body, for example in theplasma, liver or small intestine of a mammal or human.

For administration of pharmaceutically acceptable salts of the abovecompounds, the weights indicated above refer to the weight of the acidequivalent or the base equivalent of the therapeutic compound derivedfrom the salt.

In one embodiment of the present invention, the compositions ortherapeutic combinations can further comprise one or morepharmacological or therapeutic agents or drugs such as lipid-loweringagents discussed below. As used herein, “combination therapy” or“therapeutic combination” means the administration of two or moretherapeutic agents, such as a compound of Formula (I) and alipid-lowering or antihypertensive agent, to prevent or treat acondition as described above. Such administration includescoadministration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single tablet or capsule having afixed ratio of active ingredients or in multiple, separate capsules foreach therapeutic agent. Also, such administration includes use of eachtype of therapeutic agent in a sequential manner. In either case, thetreatment using the combination therapy will provide beneficial effectsin treating the condition. A potential advantage of the combinationtherapy disclosed herein may be a reduction in the required amount of anindividual therapeutic compound or the overall total amount oftherapeutic compounds that are effective in treating the condition. Byusing a combination of therapeutic agents, the side effects of theindividual compounds can be reduced as compared to a monotherapy, whichcan improve patient compliance. Also, therapeutic agents can be selectedto provide a broader range of complimentary effects or complimentarymodes of action.

Non-limiting examples of additional cholesterol biosynthesis inhibitorsfor use in the compositions, therapeutic combinations and methods of thepresent invention include squalene synthase inhibitors, squaleneepoxidase inhibitors and mixtures thereof. Non-limiting examples ofsuitable HMG CoA synthetase inhibitors include L-659,699((E,E)-11-[3′R-(hydroxy-methyl)-4′-oxo-2′R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoicacid); squalene synthesis inhibitors, for example squalestatin 1; andsqualene epoxidase inhibitors, for example, NB-598((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3′-bithiophen-5-yl)methoxy]benzene-methanaminehydrochloride) and other sterol biosynthesis inhibitors such as DMP-565.Generally, a total daily dosage of additional cholesterol biosynthesisinhibitor(s) can range from about 0.1 to about 160 mg per day, andpreferably about 0.2 to about 80 mg/day in single or 2-3 divided doses.

In another preferred embodiment, the composition or treatment comprisesthe compound of Formula (I) in combination with one or more peroxisomeproliferator-activated receptor(s) activator(s). In this embodiment,preferably the peroxisome proliferator-activated receptor activator(s)is a fibric acid derivative such as gemfibrozil, clofibrate and/orfenofibrate.

In another alternative embodiment, the compositions, therapeuticcombinations or methods of the present invention can further compriseone or more bile acid sequestrants (insoluble anion exchange resins),coadministered with or in combination with the compound of Formula (I)discussed above. Bile acid sequestrants bind bile acids in theintestine, interrupting the enterohepatic circulation of bile acids andcausing an increase in the faecal excretion of steroids. Bile acidsequestrants can lower intrahepatic cholesterol and promote thesynthesis of apo B/E (LDL) receptors that bind LDL from plasma tofurther reduce cholesterol levels in the blood. Non-limiting examples ofsuitable bile acid sequestrants include cholestyramine (astyrene-divinylbenzene copolymer containing quaternary ammonium cationicgroups capable of binding bile acids, such as QUESTRAN® or QUESTRANLIGHT® cholestyramine which are available from Bristol-Myers Squibb),colestipol (a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are availablefrom Pharmacia), and colesevelam hydrochloride (such as WelChol® Tablets(poly(allylamine hydrochloride) cross-linked with epichlorohydrin andalkylated with 1-bromodecane and (6-bromohexyl)-trimethylammoniumbromide) which are available from Sankyo). Generally, a total dailydosage of bile acid sequestrant(s) can range from about 1 to about 50grams per day, and preferably about 2 to about 16 grams per day insingle or 2-4 divided doses.

In an alternative embodiment, the compositions or treatments of thepresent invention can further comprise one or more ileal bile acidtransport (“IBAT”) inhibitors (or apical sodium co-dependent bile acidtransport (“ASBT”) inhibitors) coadministered with or in combinationwith the compound of Formula (I) discussed above. The IBAT inhibitorscan inhibit bile acid transport to reduce LDL cholesterol levels.Non-limiting examples of suitable IBAT inhibitors include benzothiepinessuch as therapeutic compounds comprising a2,3,4,5-tetrahydro-1-benzothiepine 1,1-dioxide structure such as aredisclosed in PCT Patent Application WO 00/38727 which is incorporatedherein by reference. Generally, a total daily dosage of IBATinhibitor(s) can range from about 0.01 to about 1000 mg/day, andpreferably about 0.1 to about 50 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise nicotinic acid (niacin) and/orderivatives thereof coadministered with or in combination with thecompound of Formula (I) discussed above. As used herein, “nicotinic acidderivative” means a compound comprising a pyridine-3-carboxylatestructure or a pyrazine-2-carboxylate structure, including acid forms,salts, esters, zwitterions and tautomers, where available. Examples ofnicotinic acid derivatives include niceritrol, nicofuranose and acipimox(5-methyl pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and itsderivatives inhibit hepatic production of VLDL and its metabolite LDLand increases HDL and apo A-1 levels. An example of a suitable nicotinicacid product is NIASPAN® (niacin extended-release tablets) which areavailable from Kos. Generally, a total daily dosage of nicotinic acid ora derivative thereof can range from about 500 to about 10,000 mg/day,preferably about 1000 to about 8000 mg/day, and more preferably about3000 to about 6000 mg/day in single or divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise one or more AcylCoA:CholesterolO-acyltransferase (“ACAT”) Inhibitors, which can reduce LDL and VLDLlevels, coadministered with or in combination with the compound ofFormula (I) discussed above. ACAT is an enzyme responsible foresterifying excess intracellular cholesterol and may reduce thesynthesis of VLDL, which is a product of cholesterol esterification, andoverproduction of apo B-100-containing lipoproteins. Non-limitingexamples of useful ACAT inhibitors include avasimibe, HL-004, lecimibide(DuP-128) and CL-277082(N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea).See P. Chang et al., “Current, New and Future Treatments inDyslipidaemia and Atherosclerosis”, Drugs July 2000;60(1); 55-93, whichis incorporated by reference herein. Generally, a total daily dosage ofACAT inhibitor(s) can range from about 0.1 to about 1000 mg/day insingle or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise one or more Cholesteryl EsterTransfer Protein (“CETP”) Inhibitors coadministered with or incombination with compound of Formula (I) discussed above. CETP isresponsible for the exchange or transfer of cholesteryl ester carryingHDL and triglycerides in VLDL. Non-limiting examples of suitable CETPinhibitors are disclosed in PCT Patent Application No. WO 00/38721 andU.S. Pat. No. 6,147,090, which are incorporated herein by reference.Pancreatic cholesteryl ester hydrolase (PCEH) inhibitors such asWAY-121898 also can be coadministered with or in combination with thecompound of Formula (I) discussed above. Generally, a total daily dosageof CETP inhibitor(s) can range from about 0.01 to about 1000 mg/day, andpreferably about 0.5 to about 20 mg/kg body weight/day in single ordivided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise probucol or derivatives thereof(such as AGI-1067 and other derivatives disclosed in U.S. Pat. Nos.6,121,319 and 6,147,250), which can reduce LDL levels, coadministeredwith or in combination with the compound of Formula (I) discussed above.Generally, a total daily dosage of probucol or derivatives thereof canrange from about 10 to about 2000 mg/day, and preferably about 500 toabout 1500 mg/day in single or 24 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise low-density lipoprotein (LDL)receptor activators, coadministered with or in combination with thecompound of Formula (I) discussed above. Non-limiting examples ofsuitable LDL-receptor activators include HOE402, animidazolidinyl-pyrimidine derivative that directly stimulates LDLreceptor activity. See M. Huettinger et al., “Hypolipidemic activity ofHOE-402 is Mediated by Stimulation of the LDL Receptor Pathway”,Arterioscler. Thromb. 1993; 13:1005-12.

Generally, a total daily dosage of LDL receptor activator(s) can rangefrom about 1 to about 1000 mg/day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise fish oil, which contains Omega 3fatty acids (3-PUFA), which can reduce VLDL and triglyceride levels,coadministered with or in combination with the compound of Formula (I)discussed above. Generally, a total daily dosage of fish oil or Omega 3fatty acids can range from about 1 to about 30 grams per day in singleor 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise natural water soluble fibers,such as psyllium, guar, oat and pectin, which can reduce cholesterollevels, coadministered with or in combination with the compound ofFormula (I) discussed above. Generally, a total daily dosage of naturalwater soluble fibers can range from about 0.1 to about 10 grams per dayin single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise plant sterols, plant stanolsand/or fatty acid esters of plant stanols, such as sitostanol ester usedin BENECOL® margarine, which can reduce cholesterol levels,coadministered with or in combination with the compound of Formula (I)discussed above. Generally, a total daily dosage of plant sterols, plantstanols and/or fatty acid esters of plant stanols can range from about0.5 to about 20 grams per day in single or 24 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise antioxidants, such as probucol,tocopherol, ascorbic acid, β-carotene and selenium, or vitamins such asvitamin B₆ or vitamin B₁₂, coadministered with or in combination withthe compound of Formula (I) discussed above. Generally, a total dailydosage of antioxidants or vitamins can range from about 0.05 to about 10grams per day in single or 2-4 divided doses.

In another alternative embodiment, the compositions or treatments of thepresent invention can further comprise monocyte and macrophageinhibitors such as polyunsaturated fatty acids (PUFA), thyroid hormonesincluding throxine analogues such as CGS-26214 (a thyroxine compoundwith a fluorinated ring), gene therapy and use of recombinant proteinssuch as recombinant apo E, coadministered with or in combination withthe compound of Formula (I) discussed above. Generally, a total dailydosage of these agents can range from about 0.01 to about 1000 mg/day insingle or 2-4 divided doses.

Also useful with the present invention are compositions or therapeuticcombinations that further comprise hormone replacement agents andcompositions. Useful hormone agents and compositions for hormonereplacement therapy of the present invention include androgens,estrogens, progestins, their pharmaceutically acceptable salts andderivatives thereof. Combinations of these agents and compositions arealso useful. The dosage of androgen and estrogen combinations vary,desirably from about 1 mg to about 4 mg androgen and from about 1 mg toabout 3 mg estrogen.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more obesity control medications.Useful obesity control medications include, but are not limited to,drugs that reduce energy intake or suppress appetite, drugs thatincrease energy expenditure and nutrient-partitioning agents. Suitableobesity control medications include, but are not limited to,noradrenergic agents (such as diethylpropion, mazindol,phenylpropanolamine, phentermine, phendimetrazine, phendamine tartrate,methamphetamine, phendimetrazine and tartrate); serotonergic agents(such as sibutramine, fenfluramine, dexfenfluramine, fluoxetine,fluvoxamine and paroxtine); thermogenic agents (such as ephedrine,caffeine, theophylline, and selective β3-adrenergic agonists);alpha-blocking agents; kainite or AMPA receptor antagonists;leptin-lipolysis stimulated receptors; phosphodiesterase enzymeinhibitors; compounds having nucleotide sequences of the mahogany gene;fibroblast growth factor-10 polypeptides; monoamine oxidase inhibitors(such as befloxatone, moclobemide, brofaromine, phenoxathine, esuprone,befol, toloxatone, pirlindol, amiflamine, sercloremine, bazinaprine,lazabemide, milacemide and caroxazone); compounds for increasing lipidmetabolism (such as evodiamine compounds); and lipase inhibitors (suchas orlistat). Generally, a total dosage of the above-described obesitycontrol medications can range from 1 to 3,000 mg/day, desirably fromabout 1 to 1,000 mg/day and more desirably from about 1 to 200 mg/day insingle or 2-4 divided doses.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more blood modifiers which arechemically different from the compounds of Formula (I) discussed above,for example, they contain one or more different atoms, have a differentarrangement of atoms or a different number of one or more atoms than thecompounds of Formula (I) discussed above. Useful blood modifiers includebut are not limited to anti-coagulants (argatroban, bivalirudin,dalteparin sodium, desirudin, dicumarol, lyapolate sodium, nafamostatmesylate, phenprocoumon, tinzaparin sodium, warfarin sodium);antithrombotic (anagrelide hydrochloride, bivalirudin, cilostazol,dalteparin sodium, danaparoid sodium, dazoxiben hydrochloride, efegatransulfate, enoxaparin sodium, fluretofen, ifetroban, ifetroban sodium,lamifiban, lotrafiban hydrochloride, napsagatran, orbofiban acetate,roxifiban acetate, sibrafiban, tinzaparin sodium, trifenagrel,abciximab, zolimomab aritox); fibrinogen receptor antagonists (roxifibanacetate, fradafiban, orbofiban, lotrafiban hydrochloride, tirofiban,xemilofiban, monoclonal antibody 7E3, sibrafiban); platelet inhibitors(cilostazol, clopidogrel bisulfate, epoprostenol, epoprostenol sodium,ticlopidine hydrochloride, aspirin, ibuprofen, naproxen, sulindae,idomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone,piroxicam, dipyridamole); platelet aggregation inhibitors (acadesine,beraprost, beraprost sodium, ciprostene calcium, itazigrel, lifarizine,lotrafiban hydrochloride, orbofiban acetate, oxagrelate, fradafiban,orbofiban, tirofiban, xemilofiban); hemorrheologic agents(pentoxifylline); lipoprotein associated coagulation inhibitors; FactorVIIa inhibitors (4H-31-benzoxazin4-ones, 4H-3,1-benzoxazin4-thiones,quinazolin4-ones, quinazolin4-thiones, benzothiazin4-ones,imidazolyl-boronic acid-derived peptide analogues TFPI-derived peptides,naphthalene-2-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolid in-3-(S)-yl} amidetrifluoroacetate, dibenzofuran-2-sulfonic acid{1-[3-(aminomethyl)-benzyl]-5-oxo-pyrrolidin-3-yl}-amide,tolulene-4-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolidin-3-(S)-yl}-amidetrifluoroacetate, 3,4-dihydro-1H-isoquinoline-2-sulfonic acid{1-[3-(aminoiminomethyl)-benzyl]-2-oxo-pyrrolin-3-(S)-yl}-amidetrifluoroacetate); Factor Xa inhibitors (disubstituted pyrazolines,disubstituted triazolines, substitutedn-[(aminoiminomethyl)phenyl]propylamides, substitutedn-[(aminomethyl)phenyl]propylamides, tissue factor pathway inhibitor(TFPI), low molecular weight heparins, heparinoids, benzimidazolines,benzoxazolinones, benzopiperazinones, indanones, dibasic (amidinoaryl)propanoic acid derivatives, amidinophenyl-pyrrolidines,amidinophenyl-pyrrolines, amidinophenyl-isoxazolidines, amidinoindoles,amidinoazoles, bis-arlysulfonylaminobenzamide derivatives, peptidicFactor Xa inhibitors).

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more cardiovascular agents whichare chemically different from the compounds of Formula (I) discussedabove, for example, they contain one or more different atoms, have adifferent arrangement of atoms or a different number of one or moreatoms than the compounds of Formula (I) discussed above. Usefulcardiovascular agents include but are not limited to calcium channelblockers (clentiazem maleate, amlodipine besylate, isradipine,nimodipine, felodipine, nilvadipine, nifedipine, teludipinehydrochloride, diltiazem hydrochloride, belfosdil, verapamilhydrochloride, fostedil); adrenergic blockers (fenspiride hydrochloride,labetalol hydrochloride, proroxan, alfuzosin hydrochloride, acebutolol,acebutolol hydrochloride, alprenolol hydrochloride, atenolol, bunololhydrochloride, carteolol hydrochloride, celiprolol hydrochloride,cetamolol hydrochloride, cicloprolol hydrochloride, dexpropranololhydrochloride, diacetolol hydrochloride, dilevalol hydrochloride,esmolol hydrochloride, exaprolol hydrochloride, flestolol sulfate,labetalol hydrochloride, levobetaxolol hydrochloride, levobunololhydrochloride, metalol hydrochloride, metoprolol, metoprolol tartrate,nadolol, pamatolol sulfate, penbutolol sulfate, practolol, propranololhydrochloride, sotalol hydrochloride, timolol, timolol maleate,tiprenolol hydrochloride, tolamolol, bisoprolol, bisoprolol fumarate,nebivolol); adrenergic stimulants; angiotensin converting enzyme (ACE)inhibitors (benazepril hydrochloride, benazeprilat, captopril, delaprilhydrochloride, fosinopril sodium, libenzapril, moexipril hydrochloride,pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril,spirapril hydrochloride, spiraprilat, teprotide, enalapril maleate,lisinopril, zofenopril calcium, perindopril erbumine); antihypertensiveagents (althiazide, benzthiazide, captopril, carvedilol, chlorothiazidesodium, clonidine hydrochloride, cyclothiazide, delapril hydrochloride,dilevalol hydrochloride, doxazosin mesylate, fosinopril sodium,guanfacine hydrochloride, methyidopa, metoprolol succinate, moexiprilhydrochloride, monatepil maleate, pelanserin hydrochloride,phenoxybenzamine hydrochloride, prazosin hydrochloride, primidolol,quinapril hydrochloride, quinaprilat, ramipril, terazosin hydrochloride,candesartan, candesartan cilexetil, telmisartan, amlodipine besylate,amlodipine maleate, bevantolol hydrochloride), for example HYZAAR® orCOZAAR® antihypertensive agents available from Merck & Co., Inc.;angiotensin II receptor antagonists (candesartan, irbesartan, losartanpotassium, candesartan cilexetil, telmisartan); anti-anginal agents(amlodipine besylate, amlodipine maleate, betaxolol hydrochloride,bevantolol hydrochloride, butoprozine hydrochloride, carvedilol,cinepazet maleate, metoprolol succinate, molsidomine, monatepil maleate,primidolol, ranolazine hydrochoride, tosifen, verapamil hydrochloride);coronary vasodilators (fostedil, azaclorzine hydrochloride, chromonarhydrochloride, clonitrate, diltiazem hydrochloride, dipyridamole,droprenilamine, erythrityl tetranitrate, isosorbide dinitrate,isosorbide mononitrate, lidoflazine, mioflazine hydrochloride, mixidine,molsidomine, nicorandil, nifedipine, nisoldipine, nitroglycerine,oxprenolol hydrochloride, pentrinitrol, perhexiline maleate,prenylamine, propatyl nitrate, terodiline hydrochloride, tolamolol,verapamil); diuretics (the combination product of hydrochlorothiazideand spironolactone and the combination product of hydrochlorothiazideand triamterene).

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more antidiabetic medications forreducing blood glucose levels in a human. Useful antidiabeticmredications include, but are not limited to, drugs that reduce energyintake or suppress appetite, drugs that increase energy expenditure andnutrient-partitioning agents. Suitable antidiabetic medications include,but are not limited to, sulfonylurea (such as acetohexamide,chlorpropamide, gliamilide, gliclazide, glimepiride, glipizide,glyburide, glibenclamide, tolazamide, and tolbutamide), meglitinide(such as repaglinide and nateglinide), biguanide (such as mefformin andbuformin), alpha-glucosidase inhibitor (such as acarbose, miglitol,camiglibose, and voglibose), certain peptides (such as amlintide,pramlintide, exendin, and GLP-1 agonistic peptides), and orallyadministrable insulin or insulin composition for intestinal deliverythereof. Generally, a total dosage of the above-described antidiabeticmedications can range from 0.1 to 1,000 mg/day in single or 2-4 divideddoses.

The compositions, therapeutic combinations or methods of the presentinvention can further comprise one or more treatments for Alzheimer'sDisease which are chemically different from the compounds of Formula(I). Non-limiting examples of suitable treatments which can be useful intreating Alzheimer's Disease include administration of one or more ofthe following: cholinesterase inhibitors, muscarinic receptor agonists,M2 muscarinic receptor antagonists, acetylcholine release stimulators,choline uptake stimulators, nicotinic cholinergic receptor agonists,anti-AP vaccines, γ-secretase inhibitors, β-secretase inhibitors,amyloid aggregation inhibitors, amyloid precursor protein antisenseoligonucleotides, monoamine reuptake inhibitors, human stem cells, genetherapy, nootropic agents, AMPA receptor ligands, growth factors orgrowth factor receptor agonists, anti-inflammatory agents, free radicalscavengers, antioxidants, superoxide dismutase stimulators, calciumchannel blockers, apoptosis inhibitors, caspase inhibitors, monoamineoxidase inhibitors, estrogens and estrogen receptor ligands, NMDAreceptor antagonists, Jun N-terminal kinase (JNK) inhibitors,copper/zinc chelators, 5-HT1a receptor agonists, NGF stimulators,neuroprotective agents, H3 histamine receptor antagonists, calpaininhibitors, poly ADP ribose polymerase inhibitors, prolylendopeptidaseinhibitors, calcium modulators, corticortropin releasing factor receptorantagonists, corticortropin releasing factor binding protein inhibitors,GABA modulators, GABA-A receptor antagonists, GABA-B receptorantagonists, neuroimmunophilin ligands, sigma receptor ligands, galaninreceptor ligands, imidazoline/alpha adrenergic receptor antagonists,vasoactive intestinal peptide receptor agonists, benzodiazepine receptorinverse agonists, cannabinoid receptor agonists, thyrotropin releasinghormone receptor agonists, protein kinase C inhibitors, 5-HT3 receptorantagonists, prostaglandin receptor antagonists, topoisomerase IIinhibitors, steroid receptor ligand, nitric oxide modulators, RAGEinhibitors, dopamine receptor agonists, and combinations thereof.

Mixtures of any of the pharmacological or therapeutic agents describedabove can be used in the compositions and therapeutic combinations ofthe present invention.

The pharmaceutical treatment compositions (formulations or medicaments)and therapeutic combinations of the present invention can furthercomprise one or more pharmaceutically acceptable carriers, one or moreexcipients and/or one or more additives. As used herein, the term“composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

Non-limiting examples of pharmaceutically acceptable carriers includesolids and/or liquids such as ethanol, glycerol, water and the like. Theamount of carrier in the treatment composition can range from about 5 toabout 99 weight percent of the total weight of the treatment compositionor therapeutic combination. Non-limiting examples of suitablepharmaceutically acceptable excipients and additives include non-toxiccompatible fillers, binders such as starch, disintegrants, buffers,preservatives, anti-oxidants, lubricants, flavorings, thickeners,coloring agents, emulsifiers and the like. The amount of excipient oradditive can range from about 0.1 to about 90 weight percent of thetotal weight of the treatment composition or therapeutic combination.One skilled in the art would understand that the amount of carrier(s),excipients and additives (if present) can vary.

The treatment compositions of the present invention can be administeredin any conventional dosage form, preferably an oral dosage form such asa capsule, tablet, powder, cachet, suspension or solution. Theformulations and pharmaceutical compositions can be prepared usingconventional pharmaceutically acceptable and convnentional techniques.Several examples of preparation of dosage formulations are providedbelow.

The following formulation exemplifies a dosage form of this invention.In the formulation, the term “Active Compound I” designates a compoundof Formula I described herein above.

EXAMPLE

Tablets No. Ingredient mg/tablet 1 Active Compound I 20 2 Lactosemonohydrate NF 55 3 Microcrystalline cellulose NF 20 4 Povidone (K29-32)USP 4 5 Croscarmellose sodium NF 8 6 Sodium lauryl sulfate 2 7 Magnesiumstearate NF 1 Total 110Method of Manufacture

Mix Item No. 4 with purified water in suitable mixer to form bindersolution. Spray the binder solution and then water over Items 1, 2, 6and a portion of Item 5 in a fluidized bed processor to granulate theingredients. Continue fluidization to dry the damp granules. Screen thedried granules and blend with Item No. 3 and the remainder of Item 5.Add Item No. 7 and mix. Compress the mixture to appropriate size andweight on a suitable tablet machine.

Since the present invention relates to treating conditions as discussedabove, such as reducing the plasma sterol (especially cholesterol)concentrations or levels by treatment with a combination of activeingredients wherein the active ingredients may be administeredseparately, the invention also relates to combining separatepharmaceutical compositions in kit form. That is, a kit is contemplatedwherein two separate units are combined: a pharmaceutical compositioncomprising at least one compound of Formula (I) and a separatepharmaceutical composition comprising at least one other therapeuticagent as described above. The kit will preferably include directions forthe administration of the separate components. The kit form isparticularly advantageous when the separate components must beadministered in different dosage forms (e.g., oral and parenteral) orare administered at different dosage intervals.

The treatment compositions and therapeutic combinations of the presentinvention can inhibit the intestinal absorption of cholesterol inmammals, as shown in the Example below, and can be useful in thetreatment and/or prevention of conditions, for example vascularconditions, such as atherosclerosis, hypercholesterolemia andsitosterolemia, stroke, obesity and lowering of plasma levels ofcholesterol in mammals, in particular in mammals.

In another embodiment of the present invention, the compositions andtherapeutic combinations of the present invention can inhibit sterolabsorption or reduce plasma concentration of at least one sterolselected from the group consisting of phytosterols (such as sitosterol,campesterol, stigmasterol and avenosterol), 5α-stanols (such ascholestanol, 5α-campestanol, 5α-sitostanol), cholesterol and mixturesthereof. The plasma concentration can be reduced by administering to amammal in need of such treatment an effective amount of at least onetreatment composition or therapeutic combination comprising a compoundof Formula (I) described above. The reduction in plasma concentration ofsterols can range from about 1 to about 70 percent, and preferably about10 to about 50 percent. Methods of measuring serum total bloodcholesterol and total LDL cholesterol are well known to those skilled inthe art and for example include those disclosed in PCT WO 99/38498 atpage 11, incorporated by reference herein. Methods of determining levelsof other sterols in serum are disclosed in H. Gylling et al., “SerumSterols During Stanol Ester Feeding in a Mildly HypercholesterolemicPopulation”, J. Lipid Res. 40: 593-600 (1999), incorporated by referenceherein.

Illustrating the invention are the following examples which, however,are not to be considered as limiting the invention to their details.Unless otherwise indicated, all parts and percentages in the followingexamples, as well as throughout the specification, are by weight.

EXAMPLES

Method Description:Method A:

ADDP (0.1 g, 0.39 mmol) was added to a solution of azetidinylphenol 1(0.1 g, 0.28 mmol), tributylphosphine (0.08 g, 0.39 mmol), and3-benzyloxy-propan-1-ol (42 mg, 0.255 mmol) in 1 mL of THF at 0° C. Thereaction was allowed to warm to room temperature. Another 0.5 mL of THFwas added to reduce thickening. After 3.5 h, the mixture was dilutedwith 20% ethyl acetate in hexanes and filtered through Celite to give0.078 g of ether 2 as a colorless oil after concentration.

ADDP is

1,1′-(azodicarbonyl)dipiperidine).

Reference: T. Tsunoda, Y. Yamamiya and S. Itô Tetrahedron Left., 1993,34, 1639-1642.

Method B:

Ether 2 (0.07 g, 0.134 mmol) was dissolved in 3 mL of ethyl acetate andtreated with 7 mg of 5% palladium on carbon. The mixture was stirredunder 1 atm of hydrogen gas for 3 h at room temperature. The catalystwas filtered through Celite and eluent was concentrated to give aquantitative yield of the desired alcohol.

Method C:

To a solution of alcohol (0.36 g, 0.83 mmol) in THF was added 0.272 g oftriphenylphosphine (1.04 mmol). The mixture was cooled to −20° C. and0.20 mL of diethylazodicarboxylate (0.27 g, 1.04 mmol) was addeddropwise. To this mixture was added 0.22 mL of diphenylphosphoryl azide(0.29 g, 1.04 mmol) and the reaction was allowed to warm to roomtemperature overnight. The mixture was concentrated in vacuo andchromatographed on SiO₂ eluting with 15-20% ethyl acetate in hexanes togive 0.263 g of the desired azide as a colorless oil.

Method D:

To a solution of azide (0.263 g, 0.58 mmol) in 12 mL of 1:1methanol-ethyl acetate was added 26 mg of 10% palladium on carbon. Themixture was stirred under 1 atm hydrogen gas for 5 h. The catalyst wasfiltered through Celite and concentration of the solvent gave 0.246 g ofthe desired amine 3.

Method E:

A mixture of lovastatin 4 (commercially available from Merck & Co. asMEVACOR®)(0.039g, 0.1 mmol) and 0.045 g of amine 3 (0.11 mmol) in 19 mgof pyridine was stirred for 24 h at room temperature. The reaction waschromatographed twice over SiO2 eluting with 2-5% methanol indichloromethane to give 0.028 g of the desired product 5 (m.p.=67-68°C.).

In Vivo Evaluation

The hypercholesterolemic Golden Syrian hamster was used as the in vivomodel to evaluate the oral potency and in vivo efficacy of cholesterolabsorption inhibitors. Hamsters are fed a cholesterol-containing dietfor 7 days, which results in an increase in hepatic cholesteryl esters.A compound which blocks intestinal cholesterol absorption will reducethe accumulation of hepatic cholesteryl ester levels.

Male Golden Syrian hamsters (Charles River Labs, Wilmington, Mass.) werefed Wayne rodent chow until study onset. At study onset (Day 1) animalswere separated into groups (n=4-6/group) and fed chow supplemented with0.5% by weight of cholesterol (Research Diets Inc., New Brunswick,N.J.). One group of hamsters received a dosage of 3 mg/kg of body weightof the compound of Formula (XIV) administered once daily for 7 days,starting on Day 1 via oral gavage in 0.2 ml corn oil. The control groupof hamsters received placebo corn oil in the same amount on the sameschedule. On Day 7 liver samples were taken for neutral lipid analyses.Samples of liver were lipid extracted. Lipid extracts were dried undernitrogen into HPLC sample vials, resuspended in hexane and injected ontoa Zorbax Sil (4.6×25 cm) silica column. Chromatography was performedusing an isocratic mobile phase containing 98.8% hexane and 1.2%isopropanol at a flow rate of 2 ml/min. Lipids were detected byabsorbance at 206 nm and quantitated by computer integration (SystemGold, Beckman) of elution profiles. Cholesterol concentrations weredetermined by the use of a response factor derived from a standard curveusing known amounts of cholesterol. Cholesteryl ester content ofliver-derived samples was derived from a standard curve constructedusing known amounts of cholesteryl oleate. Cholesteryl oleate was usedas the standard since this is the major cholesteryl ester speciespresent in the liver and this specific cholesteryl ester has anextinction coefficient that approximates that of a weighted average forall the cholesteryl esters present in the liver.

The reduction of hepatic cholesteryl ester accumulation is utilized as amarker for cholesterol absorption inhibition. When administered tohamsters as set forth above, the compound of Formula (XIV) reduced theaccumulation of hepatic cholesteryl esters by 16% relative to thecontrol group, based on once daily dosing for 7 days.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications that are within the spirit and scopeof the invention, as defined by the appended claims.

1. A compound represented by the structural formula (I):

or pharmaceutically acceptable isomers, salts, solvates or esters of thecompound of Formula (I), wherein in Formula (I) above: X, Y and Z can bethe same or different and each is independently selected from the groupconsisting of —CH₂—, —CH(alkyl)- and —C(alkyl)₂-; Q¹ and Q² can be thesame or different and each is independently selected from the groupconsisting of H, -G, —(C₁-C₃₀ alkylene)-G, —OR⁶, —OC(O)R⁶, —OC(O)OR⁹,—OC(O)NR⁶R⁷, and -L-M. Q³ is 1 to 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, alkynyl, -G, —(C₁-C₃₀alkylene)-G, —OR⁶, —(C₁-C₁₀ alkylene)-OR⁶, —C(O)R⁶, —(C₁-C₁₀alkylene)-C(O)R⁶, —C(O)OR⁶, —(C₁-C₁₀ alkylene)-C(O)OR, —OC(O)R⁶,—(C₁-C₁₀ alkylene)-OC(O)R⁶, —OC(O)OR⁹, —(C₁-C₁₀ alkylene)-OC(O)OR⁹,—CH═CH—C(O)R⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷,—O—C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀alkylene)-C(O)(aryl)-N₃, —OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —C(O)NR⁶R⁷,—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —(C₁-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —NR⁶R⁷, —(C₀-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁶R⁷, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂,—CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M; Q⁴ is 1 to 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, -G, —(C₁-C₃₀ alkylene)-G, —OR⁶, —(C₁-C₁₀ alkylene)-OR⁶,—C(O)R⁶, —(C₁-C₁₀ alkylene)-C(O)R⁶, —C(O)OR⁶, —(C₁-C₁₀alkylene)-C(O)OR⁶, —OC(O)R⁶, —(C₁-C₁₀ alkylene)-OC(O)R⁶, —OC(O)OR⁹,—(C₁-C₁₀ alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶, —CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀ alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷,—O—C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀alkylene)-C(O)(aryl)-N₃, —OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —C(O)NR⁶R⁷,—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —(C₁-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —NR⁶R⁷, —(C₁-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁸, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M; Q⁵ is 1 to 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,alkynyl, -G, —(C₁-C₃₀ alkylene)-G, —OR⁶, —(C₁-C₁₀ alkylene)-OR⁶,—C(O)R⁶, —(C₁-C₁₀ alkylene)-C(O)R⁶, —C(O)OR⁶, —(C₁-C₁₀alkylene)-C(O)OR⁶, —OC(O)R⁶, —(C₁-C₁₀ alkylene)-OC(O)R⁶, —(C₁-C₁₀alkylene)-OC(O)OR⁹, —CH═CH—C(O)R⁶, —CH═CH—C(O)OR⁶,

—O—(C₁-C₁₀alkylene)-OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)R⁶, —O—(C₁-C₁₀alkylene)-C(O)OR⁶, —CN, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷,—O—C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀ alkylene)-C(O)NR⁶NR⁷C(O)OR⁶, —O—(C₁-C₁₀alkylene)-C(O)(aryl)-N₃, —OC(O)—(C₁-C₁₀ alkylene)-C(O)OR⁶, —C(O)NR⁶R⁷,—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)NR⁶R⁷, —(C₁-C₁₀alkylene)-OC(O)NR⁶R⁷, —NO₂, —NR⁶R⁷, —(C₁-C₁₀ alkylene)-NR⁶R⁷, —O—(C₂-C₁₀alkylene)-NR⁶R⁷, —NR⁶C(O)R⁷, —NR⁶C(O)OR⁹, —NR⁶C(O)NR⁷R⁶, —NR⁶S(O)₀₋₂R⁹,—N(S(O)₀₋₂R⁹)₂, —CHNOR⁶, —C(O)NR⁶R⁷, —C(O)NR⁶NR⁶R⁷, —S(O)₀₋₂NR⁶R⁷,—S(O)₀₋₂R⁹, —O—C(O)—(C₁-C₁₀ alkylene)-C(O)NR⁶R⁷, —OC(O)—(C₁-C₁₀alkylene)-NR⁶C(O)O-(alkylaryl), —P(O)(OR¹⁰)₂, —(C₁-C₁₀alkylene)-OSi(alkyl)₃, —CF₃, —OCF₃, halo, alkoxyalkoxy,alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy, alkoxyarylalkoxy,alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl, arylalkyl, aryloxy,arylalkoxy, aroyl, aroyloxy, aroylaroyloxy, arylalkoxycarbonyl,benzoylbenzoyloxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy,dioxolanyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,heterocyclylcarbonylalkoxy and -L-M; wherein optionally one or morecarbon atoms of the —(C₁-C₃₀ alkylene)- radical of Q¹, Q², Q³, Q⁴ and Q⁵is independently replaced by —O—, —C(O)—, —CH═CH—,

—N(alkyl)-, —N(alkylaryl)- or —NH—; G is selected from the groupconsisting of a sugar residue, disugar residue, trisugar residue,tetrasugar residue, sugar acid, amino sugar, and oligopeptide residuecomprising 2 to 9 amino acids, wherein optionally the sugar residue,disugar residue, trisugar residue, tetrasugar residue, sugar acid, aminosugar, or oligopeptide residue of G is substituted with -L-M; L isselected from the group consisting of

wherein Me is methyl; M is selected from the group consisting of

R² and R³ can be the same or different and each is independentlyselected from the group consisting of hydrogen, alkyl and aryl; R⁶, R⁷and R⁸ can be the same or different and each is independently selectedfrom the group consisting of hydrogen, alkyl, aryl and arylalkyl; andeach R⁹ is independently alkyl, aryl or arylalkyl. each R¹⁰ isindependently H or alkyl; q is 0 or 1; r is 0 or 1; m, n and p areindependently selected from 0, 1, 2, 3 or 4; provided that at least oneof q and r is 1, and the sum of m, n, p, q and r is 1, 2, 3, 4, 5 or 6;and provided that when p is 0 and r is 1, the sum of m, q and n is 1, 2,3, 4 or 5; x1 is 1 to 10; x2 is 1 to 10; x3 is 1 to 10; x4 is 1 to 10;x5 is 1 to 10; x6 is 1 to 10; and x7 is 1 to 10; with the proviso thatat least one of Q¹, Q², Q³, Q⁴ and Q¹ is -L-M or the sugar residue,disugar residue, trisugar residue, tetrasugar residue, sugar acid, aminosugar, or oligopeptide residue of G is substituted with -L-M, andwherein each of the above alkyl, alkenyl, alkynyl alkylene,alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxycarbonylalkoxy,alkoxyarylalkoxy, alkoxyiminoalkyl, alkyldioyl, allyloxy, aryl,arylalkyl, aryloxy, arylalkoxy, aroyl, aroyloxy, aroylaroyloxy,arylalkoxycarbonyl, benzoylbenzoyloxy, heteroaryl, heteroarylalkyl,heteroarylalkoxy, dioxolanyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, or heterocvclylcarbonylalkoxy groups, whenpresent, is independently substituted or unsubstituted.
 2. The compoundaccording to claim 1, wherein m, n and r are each zero, q is 1, p is 2,and Z is —CH₂—.
 3. The compound according to claim 1, wherein m, n and rare each zero, q is 1, p is 2, and Z is —CH₂—, Q¹ is —OR⁶, wherein R⁶ ishydrogen and Q⁵ is fluorine.
 4. The compound according to claim 1,wherein R² and R³ are each hydrogen.
 5. The compound according to claim1, wherein Q¹ and Q² are each independently selected from the groupconsisting of —OR⁶, —O(CO)R⁶, —O(CO)OR⁹ and —O(CO)NR⁶R⁷.
 6. The compoundaccording to claim 1, wherein Q⁴ is halo or —OR⁶.
 7. The compoundaccording to claim 1, wherein Q¹ is —OR⁶ wherein R⁶ is H.
 8. Thecompound according to claim 1, wherein Q¹, Q², Q³, Q⁴ or Q⁵ is -L-M. 9.The compound according to claim 1, wherein Q¹, Q², Q³, Q⁴ or Q⁵ is -G or—(C₁-C₃₀ alkylene)-G.
 10. The compound according to claim 1, wherein Gis selected from the group consisting of:

wherein R, R^(a) and R^(b) can be the same or different and each isindependently selected from the group consisting of H, —OH, halo, —NH₂,azido, alkoxyalkoxy or —W—R³⁰; W is independently selected from thegroup consisting of —NH—C(O)—, —O—C(O)—, —O—C(O)—N(R³¹)—,—NH—C(O)—N(R³¹)— and —O—C(S)—N(R³¹)—; R^(2a) and R^(6a) can be the sameor different and each is independently selected from the groupconsisting of H, alkyl, acetyl, aryl and arylalkyl; R^(3a), R^(4a),R^(5a), R^(7a), R^(3b) and R^(4b) can be the same or different and eachis independently selected from the group consisting of H, alkyl, acetyl,arylalkyl, —C(O)alkyl and —C(O)aryl; R³⁰ is independently selected fromthe group consisting of R³²-substituted T, R³²-substituted-T-alkyl,R³²-substituted-alkenyl, R³²-substituted-alkyl,R³²-substituted-cycloalkyl and R³²-substituted-cycloalkylalkyl; R⁻isindependently selected from the group consisting of H and alkyl; T isindependently selected from the group consisting of phenyl, furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,benzothiazolyl, thiadiazolyl, pyrazolyl, imidazolyl and pyridyl; R³² is1 to 3 substituents which are each independently selected from the groupconsisting of H, halo, alkyl, —OH, phenoxy, —CF₃, —NO₂, alkoxy,methylenedioxy, oxo, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,—N(CH₃)₂, —C(O)—NHalkyl, —C(O)—N(alkyl)₂, —C(O)-alkyl, —C(O)—alkoxy andpyrrolidinylcarbonyl; or R³² is a covalent bond and R³¹, the nitrogen towhich it is attached and R³² form a pyrrolidinyl, piperidinyl,N-methyl-piperazinyl, indolinyl or morpholinyl group, or aalkoxycarbonyl-substituted pyrrolidinyl, piperidinyl,N-methylpiperazinyl, indolinyl or morpholinyl group.
 11. The compoundaccording to claim 10, wherein G is selected from:

wherein Ac is acetyl and Ph is phenyl.
 12. The compound according toclaim 1, wherein optionally one or more carbon atoms of the —(C₁-C₃₀alkylene)- radical of Q¹, Q², Q³, Q⁴ and Q⁵ is independently replaced by—O—.
 13. The compound according to claim 1, wherein L is


14. The compound according to claim 1, wherein M is


15. The compound according to claim 1, wherein M is


16. The compound according to claim 1, wherein M is


17. The compound according to claim 1, wherein M is


18. The compound according to claim 1, wherein M is


19. The compound according to claim 1, which is selected from the groupconsisting of


20. A pharmaceutical composition for the treatment of atherosclerosis,hypercholesterolemia, sitosterolemia, diabetes mellitus, obesity,stroke, lowering a concentration of cholesterol phvtosterol or 5α-stanolin plasma of a mammal, treating demyelination or treating Alzheimer'sdisease and/or regulating levels of amyloid β peptides in a subjectcomprising a therapeutically effective amount of a compound of claim 1in a pharmaceutically acceptable carrier.
 21. A pharmaceuticalcomposition comprising a cholesterol-lowering effective amount of acompound of claim 1 in a pharmaceutically acceptable carrier.
 22. Amethod of treating atherosclerosis, hypercholesterolemia,sitosterolemia, diabetes mellitus, obesity, stroke, lowering aconcentration of cholesterol, phvtosterol or 5α-stanol in plasma of amammal, treating demyelination or treating Alzheimer's disease orregulating a level of an amyloid β peptide in a subject comprising thestep of administering to a subject in need of such treatment aneffective amount of a compound of claim
 1. 23. A method of loweringcholesterol level in plasma of a mammal in need of such treatmentcomprising administering a pharmaceutically effective amount of thecompound of claim 1.